RESUMO
A series of novel thiazole-containing amides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent and selective PfFPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were progressed to mouse in vivo PK studies and demonstrated adequate free drug exposure to warrant further investigation.
Assuntos
Antimaláricos/farmacologia , Difosfonatos/farmacologia , Inibidores Enzimáticos/farmacologia , Farnesiltranstransferase/antagonistas & inibidores , Geraniltranstransferase/antagonistas & inibidores , Plasmodium falciparum/efeitos dos fármacos , Antimaláricos/síntese química , Antimaláricos/química , Difosfonatos/síntese química , Difosfonatos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Farnesiltranstransferase/metabolismo , Geraniltranstransferase/metabolismo , Estrutura Molecular , Testes de Sensibilidade Parasitária , Plasmodium falciparum/enzimologia , Relação Estrutura-AtividadeRESUMO
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Assuntos
Amidas/farmacologia , Carbazóis/farmacologia , Criptocromos/metabolismo , Descoberta de Drogas , Hipoglicemiantes/farmacologia , Ureia/farmacologia , Amidas/síntese química , Amidas/química , Animais , Carbazóis/química , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Masculino , Camundongos , Estrutura Molecular , Obesidade/tratamento farmacológico , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
Assuntos
Carbazóis/química , Criptocromos/química , Hipoglicemiantes/química , Sulfonamidas/química , Animais , Glicemia/análise , Linhagem Celular Tumoral , Criptocromos/genética , Criptocromos/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Reporter , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Relação Estrutura-Atividade , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
Assuntos
Benzimidazóis/farmacologia , Ácidos Carboxílicos/farmacologia , Inibidores Enzimáticos/farmacologia , Peptidilprolil Isomerase/antagonistas & inibidores , Fosfatos/química , Benzimidazóis/síntese química , Benzimidazóis/química , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Domínio Catalítico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA , Peptidilprolil Isomerase/metabolismo , Relação Estrutura-AtividadeRESUMO
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Assuntos
Ativadores de Enzimas/química , Glucoquinase/metabolismo , Pirimidinonas/síntese química , Regulação Alostérica , Motivos de Aminoácidos , Animais , Sítios de Ligação , Modelos Moleculares , Pirimidinonas/química , RatosRESUMO
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteína Quinase 8 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Relação Estrutura-AtividadeRESUMO
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.
Assuntos
Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Tetra-Hidroisoquinolinas/síntese química , Tetra-Hidroisoquinolinas/farmacocinética , Administração Oral , Animais , Química Farmacêutica/métodos , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Ligantes , Taxa de Depuração Metabólica , Modelos Químicos , Ratos , Relação Estrutura-Atividade , Tetra-Hidroisoquinolinas/químicaRESUMO
Narcolepsy type 1 (Na-1) and 2 (Na-2) are characterized by an inability to sustain wakefulness and are likely caused by degeneration of orexin neurons. Near complete orexin neurodegeneration depletes orexin-A from the cerebrospinal fluid and produces Na-1. The pathophysiology of Na-2 is less understood but has been hypothesized to be due to less extensive loss of orexin neurotransmission. The orexin-tTA; TetO diphtheria toxin A mouse allows conditional control over the extent and timing of orexin neurodegeneration. To evaluate partial ablation of the orexin field as a model of Na-2, orexin-A positive cell counts and sleep/wake phenotypes (determined by piezoelectric monitoring) were correlated within individual mice after different protocols of diet-controlled neurodegeneration. Partial ablations that began during the first 8 days of study were 14% larger than partial ablations induced during the last 8 days of study, 6 weeks later and prior to sacrifice of all mice, suggesting orexin-A positive cell death continued despite the resumption of conditions intended to keep orexin neurons intact. Sleep/wake of mice with 71.0% orexin-A positive cell loss, initiated at the beginning of study, resembled that of orexin-intact controls more than mice with near complete neurodegeneration. Conversely, mice with 56.6% orexin-A positive cell loss, created at the end of study, had sleep/wake phenotypes that were similar to those of mice with near complete orexin-A positive cell loss. Collectively, these results suggest that compensatory wake-promotion develops in mice that have some critical portion of their orexinergic system remaining after partial ablation.
Assuntos
Modelos Animais de Doenças , Narcolepsia/genética , Doenças Neurodegenerativas/genética , Orexinas/genética , Fenótipo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Narcolepsia/metabolismo , Narcolepsia/fisiopatologia , Doenças Neurodegenerativas/metabolismo , Neurônios/fisiologia , Neuropeptídeos/deficiência , Neuropeptídeos/genética , Orexinas/deficiência , Sono/fisiologia , Vigília/fisiologiaRESUMO
A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.
RESUMO
In only seven steps a formal synthesis of enantiomerically enriched (+)-anatoxin-a has been achieved. This was accomplished by utilizing a highly enantioselective desymmetrization of the eight-membered ring ketone 1 to form 2, and a novel cascade reaction to construct the 9-azabicyclo[4.2.1]nonane skeleton.
RESUMO
As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.
RESUMO
A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling.
Assuntos
Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Piridinas/química , Piridinas/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Linhagem Celular Tumoral , Diabetes Mellitus/sangue , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/patologia , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Masculino , Camundongos , Estrutura Molecular , PPAR alfa/metabolismo , PPAR gama/metabolismo , Piridinas/síntese química , Piridinas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.